Linezolid is the generic name for (S)—N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide. It has been shown to be effective in a number of animal models as an anti-microbial agent. The PK/PD relationship established in a mouse thigh infection model showed that the major parameter determining efficacy was the time above MIC. Linezolid is known to be a useful antimicrobial agent that is effective against a number of human and veterinary pathogens, including Gram-positive bacteria and certain Gram-negative and anaerobic bacteria. See U.S. Pat. No. 5,688,792 and International Application No. WO 95/07271.
In clinical trials, linezolid has been shown effective in the treatment of the following infections: Vancomycin-Resistant Enterococcus faecium; Nosocomial pneumonia due to Staphylococcus aureus and Streptococcus pneumoniae; complicated skin and skin structure infections caused by Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae; uncomplicated skin and skin structure infections caused by Staphylococcus aureus or Streptococcus pyogenes; and community-acquired pneumonia caused by Streptococcus pneumoniae or Staphylococcus aureus. (Barbachyn, M R et al., U.S. Pat. No. 5,688,792 to Pharmacia & Upjohn Co.; ZYVOX Label revised July 2006).
The recommended human dose is 600 mg every 12 hours for Vancomycin-resistant Enterococcus faecium, including bacteremia; nosocomial pneumonia; complicated skin and skin structure infections; and community-acquired pneumonia, including bacteremia. A dose of 400 mg BID is recommended for uncomplicated skin and skin structure infections. In clinical trials, this dose was shown to exceed the MIC90 for Staphylococcus aureus at trough. The PK/PD relationship in humans has not been clearly established. In one study, AUC/MIC was found to be the efficacy predictor; however, this PK/PD predictor was considered to be not reliable. Linezolid shows nonlinear kinetics at higher doses. Doses of 725 mg three times a day could not be tolerated due to an increase in serum creatinine. Myelosuppression has been reported in patients receiving linezolid. The myelosuppression is reversible and patients receiving linezolid should be monitored weekly. Although the PK/PD relationship for linezolid in humans is not well established, it would clearly be advantageous to identify a compound with a longer serum half-life that could maintain exposure levels above MIC at similar or lower doses. This would allow for a lower BID dose while maintaining the required MIC or for administration of higher dosage QD which would maintain the required MIC, while reducing AUC.
Metabolism of linezolid has been studied in mice, rats, dogs and humans where two major metabolic pathways have been identified. The major metabolites excreted are the carboxylic acids known as M4 and M6 resulting from hydrolysis of the lactone and lactam rings, respectively, that are formed by oxidations of the morpholine group. These metabolites are inactive. In humans, the principal metabolic pathway is the lactone pathway. See Slatter, J G et al., Xenobiotica 2002, 32, p. 907 and Drug Metab Dispos 2001, 29, p. 1136. Approximately 35% of an administered dose in humans is found in the urine as the parent compound while 50% of the dose is accounted for as the two metabolites. The oxidation of the morpholine ring is not due to Cyp enzymes. In vitro studies showed that linezolid is not a substrate, inhibitor, or inducer of clinically relevant Cyp isoforms (1A2; 2C9; 2C19; 2D6; 2E1; 3A4). See US NDA No. 02130.
The N-oxide of linezolid is also being investigated in pre-clinical trials as an anti-bacterial agent.
It is therefore desirable to create a compound displaying the beneficial activities of linezolid, that may also have other benefits, e.g., reduced adverse side effects, with a decreased metabolic liability, to further extend its pharmacological effective life, enhance patient compliance and, potentially, to decrease population pharmacokinetic variability and/or decrease its potential for dangerous drug-drug interactions.